There are many systems and devices available for detecting a wide variety of analytes in various media. Most of these systems and devices are relatively expensive and require a trained technician to perform the test. There are many cases where it would be advantageous to be able to rapidly and inexpensively determine if an analyte were present. What is needed is a system that is easy and inexpensive to manufacture and is capable of reliable and sensitive detection of analytes.
Sandstrom et al., 24 Applied Optics 472, 1985, describe use of an optical substrate of silicon with a layer of silicon monoxide and a layer of silicon formed as dielectric films. They indicate that a change in film thickness changes the properties of the optical substrate to produce different colors related to the thickness of the film. The thickness of the film is related to the color observed and a film provided on top of an optical substrate may produce a visible color change. The authors indicate that a mathematical model can be used to quantitate the color change, and that “[c]alculations performed using the computer model show that very little can be gained in optical performance from using a multilayer structure . . . but a biolayer on the surface changes the reflection of such structures very little since the optical properties are determined mainly by the interfaces inside the multilayer structure. The most sensitive system for detection of biolayers is a single layer coating, while in most other applications performance can be improved by additional dielectric layers.”
Sandstrom et al., go on to indicate that slides formed from metal oxides on metal have certain drawbacks, and that the presence of metal ions can also be harmful in many biochemical applications. They indicate that the ideal top dielectric film is a 2-3 nm thickness of silicon dioxide which is formed spontaneously when silicon monoxide layer is deposited in ambient atmosphere, and that a 70-95 nm layer silicon dioxide on a 40-60 nm layer of silicon monoxide can be used on a glass or plastic substrate. They also describe formation of a wedge of silicon monoxide by selective etching of the silicon monoxide, treatment of the silicon dioxide surface with dichlorodimethylsilane, and application of a biolayer of antigen and antibody. From this wedge construction they were able to determine film thickness with an ellipsometer, and note that the “maximum contrast was found in the region about 65 nm where the interference color changed from purple to blue.”
U.S. Pat. No. 5,512,131 issued to Kumar et al. describes a device that includes a polymer substrate having a metal coating. An analyte-specific receptor layer is stamped on the coated substrate. The device is used in a process for stamping or as a switch. A diffraction image is generated when an analyte binds to the device. A visualization device, such as a spectrometer, is then used to determine the presence of the diffraction image.
However, the device described by Kumar et al. has several disadvantages. One disadvantage is that a complex visualization apparatus is needed to view any diffraction image.
U.S. Pat. No. 5,482,830 to Bogart, et al., describes a device that includes a substrate which has an optically active surface exhibiting a first color in response to light impinging thereon. This first color is defined as a spectral distribution of the emanating light. The substrate also exhibits a second color which is different from the first color (by having a combination of wavelengths of light which differ from that combination present in the first color, or having a different spectral distribution). The second color is exhibited in response to the same light when the analyte is present on the surface. The change from one color to another can be measured either by use of an instrument, or by eye. Such sensitive detection is an advance over the devices described by Sandstrom and Nygren, supra, and allow use of the devices in commercially viable and competitive manner.
However, the method and device described in the Bogart, et al. patent has several disadvantages. One disadvantage is the high cost of the device. Another problem with the device is the difficulty in controlling the various layers that are placed on the wafer so that one obtains a reliable reading.
Patent WO 94/13835, issued to Bogdanski et al., describes a method and system for detecting macromolecules. The system includes a probe that is a former of predetermined dimensions such that it diffracts light in a known pattern. Upon binding by a macromolecule (e.g., analyte), the position of the diffraction peaks will change due to this binding.
Thus, the system must include a more complex detector and analyzer to detect changes in a diffraction pattern. In comparison, the current diffraction-based system described is detecting the formation of a diffraction pattern or image, so that only the appearance of diffracted light must be detected. Therefore, one disadvantage of the method and system described by Bogdanski et al. is that a more complex apparatus is needed to detect changes in the diffraction pattern. Another disadvantage is the more complex methods required to prepare the probe, which involve multiple steps with photoresist and/or etching steps conducted on a brittle, silicon dioxide surface; these methods are not amenable for a full-scale manufacturing process due to high scale capital costs.
U.S. Pat. No. 5,196,350 to Backman, et al., describes an optical detection method that uses an immunoassay device along with a mask that produces a diffraction pattern. The immunoassay device is placed between the mask and light source, so that binding by the analyte causes a change in the diffraction or interference pattern caused by the mask. Thus, this patent has similar disadvantages as the Bogdanski patent since it uses a method based on detecting changes in a diffraction pattern, rather than formation of one, due to binding. This makes analysis more complex, since these changes are more subtle than a simple yes/no of a diffraction image being formed in the presence of an analyte.
U.S. Pat. No. 4,992,385 to Godfrey, et al., describes a method to prepare a diffraction grating with a thin polymer film, for subsequent use as a sensing device. The sensing device then requires the use of a spectrophotometric technique during the assay to detect changes in its optical properties due to analyte binding. Thus, as with the previous two patents, this patent also involves a more complex detection method since it must detect changes in a diffraction pattern, rather than simple formation of a pattern due to the analyte.
Some commercial lateral flow technologies have been used which employ latex bead technology. These technologies are currently employed in many of the commercially-available home diagnostic kits (e.g. pregnancy and ovulation kits). These kits use colored beads which accumulate in a defined “capture zone” until the amount of beads becomes visible to the unaided eye. However, these systems lack the requisite sensitivity to test for many analytes, since a much larger number of latex beads must bind in the capture zone to be visible to the naked eye than that required to cause diffraction in the same size zone. Theoretically, the number of beads needed is about 2 to 3 orders of magnitude higher than the number of beads required by the sensors of the present invention.
There have been several novel inventions directed to the use of biosensing devices to detect analytes. Some of these biosensors have a self-assembling monolayer and have been used to detect analytes. These types of devices are set forth in U.S. Pat. Nos. 5,922,550 and 6,060,256. Other devices having a self-assembling monolayer and using microparticle technology have been used to detect smaller analytes and are set forth in U.S. Pat. No. 6,221,579 B1. Finally, some sensing devices have been provided that incorporate non-self-assembling materials and again provide a diffraction image that can be seen with an unaided eye. This type of device is set forth in U.S. patent application Ser. No. 09/213,713. However, the present invention enhances the ease-of-use and/or accuracy of these biosensing devices by generally providing a faster, more accurate interpretation of the results of these devices.
Accordingly, what is needed is an analyzer that may be used with various diffraction-based diagnostic systems to help determine the presence of an analyte in a quick and accurate manner. Also what is needed is a method of using this analyzer to quickly and accurately determine the presence of an analyte in a given sample.